Genetic Regulation of Seizure-Induced Neurogenesis

癫痫引起的神经发生的基因调控

• 批准号: 6720120
• 负责人: PAULA E SCHAUWECKER
• 金额: $ 19.61万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720120
• 关键词: biotechnology; brain injury; cerebral ventricles; dentate gyrus; epilepsy; functional /structural genomics; genetic regulation; genetic strain; genotype; inbreeding; kainate; laboratory mouse; nervous system regeneration; neurogenetics; olfactory lobe; prosencephalon

DESCRIPTION (provided by applicant): The goal of this proposal is to determine whether allelic variation of excitotoxic cell death-vulnerable or -resistant inbred mouse strains modulates basal and seizure-induced adult forebrain neurogenesis. Recent studies suggest that aberrant regulation of persistent neurogenesis in the adult contributes to hippocampal hyperexcitability and cognitive problems associated with temporal lobe epilepsy. Despite the intense interest in persistent forebrain neural stem cells and their potential utility for brain repair therapies, little is known about the regulation of neurogenesis in the intact and injured brain. We (Dr. J. Parent) and others recently have found that experimental seizures increase neurogenesis and induce ectopic neuroblast migration in the adult rodent forebrain. The molecular mechanisms underlying these effects remain unknown. We (Dr. P. Schauwecker) have also discovered that certain inbred strains of mice differ markedly in the extent of cell death after kainic acid (KA)-induced status epilepticus (SE). By combining two cross disciplinary approaches to address altered network function in epileptogenesis, we plan to investigate the influence of genetic variation and cell death on adult neurogenesis. This collaborative proposal, a response to the program announcement for Exploratory awards in Epilepsy Research for Junior Investigators, will test two hypotheses: (1) Adult murine dentate gyrus and subventricular zone (SVZ) neurogenesis are influenced by allelic variation; and (2) Tissue injury is required to stimulate neurogenesis and ectopic neuroblast migration in the adult mouse forebrain. The specific aims are: 1) To determine whether basal adult hippocampal neurogenesis varies in mice resistant (C57BL/6) or susceptible (FVB/N) to seizure-induced cell death; 2) To establish whether SVZ-olfactory bulb neurogenesis is differentially regulated in adult C57BL/6 and FVB/N mice; 3) To determine whether seizure-induced dentate gyrus neurogenesis is triggered by injury using our model of genetically-defined murine strains; and 4) To determine whether seizure-induced SVZ neurogenesis or ectopic neuroblast migration differs between KA-induced cell death susceptible or resistant mice. The results of this collaboration will provide further insight into novel stem cell treatments for epilepsy and aid in determining effective preventative strategies and rational therapeutic designs for this neurological disorder.

描述（由申请人提供）：本提案的目的是确定兴奋毒性细胞死亡易感或抗性近交小鼠品系的等位基因变异是否调节基础和癫痫诱导的成年前脑神经发生。 最近的研究表明，成人持续性神经发生的异常调节会导致海马过度兴奋和与颞叶癫痫相关的认知问题。 尽管人们对持久性前脑神经干细胞及其在大脑修复疗法中的潜在用途产生了浓​​厚的兴趣，但人们对完整和受损大脑中神经发生的调节知之甚少。 我们（J. Parent 博士）和其他人最近发现，实验性癫痫发作会增加成年啮齿动物前脑中的神经发生并诱导异位神经母细胞迁移。 这些效应背后的分子机制仍然未知。 我们（P. Schauwecker 博士）还发现，某些近交系小鼠在红藻氨酸 (KA) 诱导的癫痫持续状态 (SE) 后细胞死亡的程度存在显着差异。 通过结合两种跨学科方法来解决癫痫发生中网络功能的改变，我们计划研究遗传变异和细胞死亡对成人神经发生的影响。 这项合作提案是对初级研究者癫痫研究探索性奖项计划公告的回应，将测试两个假设：（1）成年小鼠齿状回和室下区（SVZ）神经发生受到等位基因变异的影响； (2)刺激成年小鼠前脑中的神经发生和异位神经母细胞迁移需要组织损伤。 具体目标是： 1) 确定对癫痫诱导的细胞死亡具有抵抗性 (C57BL/6) 或易感性 (FVB/N) 的小鼠的基础成年海马神经发生是否存在差异； 2) 确定成年C57BL/6和FVB/N小鼠的SVZ嗅球神经发生是否受到差异性调节； 3）使用我们的基因定义的小鼠品系模型来确定癫痫发作诱导的齿状回神经发生是否是由损伤引发的； 4) 确定癫痫发作诱导的 SVZ 神经发生或异位神经母细胞迁移在 KA 诱导的细胞死亡易感或耐药小鼠之间是否存在差异。 此次合作的结果将进一步深入了解癫痫的新型干细胞治疗方法，并有助于确定这种神经系统疾病的有效预防策略和合理的治疗设计。